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Identification of Microorganisms Using Nucleic Acid Probes

Policy Number: MP-548

Latest Review Date: August 2022

Category: Laboratory

POLICY:

Effective for dates of service on or after July 26, 2022:

The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) may be considered medically necessary for the following microorganisms (see table at the end of this section for details on coding):

  • Bartonella henselae or quintana
  • Candida species
  • Chlamydia pneumoniae
  • Chlamydia trachomatis
  • Clostridium difficile
  • Enterococcus, vancomycin-resistant (e.g., enterococcus vanA, vanB)
  • Enterovirus
  • Gardnerella vaginalis
  • Gastrointestinal pathogen panels (GIPP)
  • Herpes simplex virus
  • Human papillomavirus (high risk type)
  • Influenza virus
  • Legionella pneumophila
  • Mycobacterium species
  • Mycobacterium tuberculosis
  • Mycobacterium avium intracellulare
  • Mycoplasma pneumoniae
  • Neisseria gonorrhoeae
  • Orthopoxvirus (Monkeypox)
  • Respiratory virus panel
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Staphylococcus aureus
  • Staphylococcus aureus, methicillin resistant
  • Streptococcus, group A
  • Streptococcus, group B
  • Tick-borne bacteria
  • Trichomonas vaginalis
  • Zika virus

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) may be considered medically necessary for the following microorganisms:

  • Cytomegalovirus
  • Hepatitis B virus
  • Hepatitis C virus
  • HIV-1
  • HIV-2
  • Human herpes virus-6

The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load for microorganisms that are not included in the above list of microorganisms is considered investigational, including, but not limited to:

  • Hepatitis G virus
  • Human papillomavirus (low risk type)

The use of nucleic acid testing expanded panels using a direct or amplified probe technique with or without quantification of viral load is considered investigational for the following microorganisms, including, but not limited to:

  • Bacterial Vaginosis (BV) Panel
  • Infectious Disease (fungus and/or bacteria) Panel
  • Genitourinary Pathogen Panel

Multitarget polymerase chain reaction testing for the diagnosis of bacterial vaginosis is considered investigational.

CURRENT CODING:

CPT Codes:

The table below provides a list of CPT codes for various nucleic acid probes.

Table. CPT Codes for Nucleic Acid Probes

Pathogen

Direct Probe

Amplified Probe

Quantification

Anaplasma phagocytophilum   87468 (Med Nec)  

Babesia microti

  87469 (Med Nec)  

Bartonella henselae or quintana

 

87471 (Med Nec)

87472 (Inv)

0301U, 0302U (Inv)

Bacterial vaginosis

  0352U (Inv)

81513-81514 (Inv)

Blood stream pathogen identification

 

87154 (Med Nec)

 

Borrelia borgdorferia

87475 (Med Nec)

87476 (Med Nec)

 

Borrelia miyamotoi

  87478 (Med Nec)  

Candida speciesb

87480 (Med Nec)

87481 (Med Nec)

0068U (Med Nec)

87482 (Inv)

Central Nervous System Pathogen Panel

 

87483 (Med Nec)

0323U (Inv)

Chlamydia pneumoniae

87485 (Med Nec)

87486 (Med Nec)

87487 (Inv)

Chlamydia trachomatis

87490 (Med Nec)

87491 (Med Nec)

0353U (Med Nec)

87492 (Inv)

Clostridium difficile

87493 (Med Nec)

   

Cytomegalovirus

87495 (Med Nec)

87496 (Med Nec)

87497 (Med Nec)

Ehrlichia chaffeensis

  87484 (Med Nec)  

Enterococcus, Vancomycin resistant (e.g., enterococcus van A, van B)

 

87500 (Med Nec)

 

Enterovirus

 

87498 (Med Nec)

 

Gardnerella vaginalis

87510 (Med Nec)

87511 (Med Nec)

87512 (Inv)

Gastrointestinal Pathogen Panel

 

87505-87507 (Med Nec)

0097U (Med Nec) (code deleted eff 4/1/22)

 

Genitourinary Pathogen Panel

 

0321U (Inv)

 

Hepatitis B

 

87516 (Med Nec)

87517 (Med Nec)

Hepatitis C

87520 (Med Nec)

87521 (Med Nec)

87522 (Med Nec)

Hepatitis G

87525 (Inv)

87526 (Inv)

87527 (Inv)

Herpes simplex virus

87528 (Med Nec)

87529 (Med Nec)

87530 (Inv)

Human Herpes virus-6

87531 (Med Nec)

87532 (Med Nec)

87533 (Med Nec)

Human Immunodeficiency Virus 1 (HIV-1)

87534 (Med Nec)

87535 (Med Nec)

87536 (Med Nec)

Human Immunodeficiency Virus 2 (HIV-2)

87537 (Med Nec)

87538 (Med Nec)

87539 (Med Nec)

Human Papillomavirus (HPV)

 

87623 (Inv) (low-risk type)

87624-87625 (Med Nec) (high-risk type)

0354U (Med Nec) (high-risk type)

Infectious Agent detection and identification

   

0112U (Inv)

Infectious disease panel (fungus and/or bacteria)

 

0140U-0142U (Inv)

 

Influenza virus

 

87501-87503 (Med Nec)

 

Legionella pneumophila

87540 (Med Nec)

87541 (Med Nec)

87542 (Inv)

Mycobacterium species

87550 (Med Nec)

87551 (Med Nec)

87552 (Inv)

Mycobacterium tuberculosis

87555 (Med Nec)

87556 (Med Nec)

87557 (Inv)

Mycobacterium avium intracellulare

87560 (Med Nec)

87561 (Med Nec)

87562 (Inv)

Mycoplasma pneumoniae

87580 (Med Nec)

87581 (Med Nec)

87582 (Inv)

Neisseria gonorrhoeae

87590 (Med Nec)

87591 (Med Nec)

87592 (Inv)

Orthopoxvirus (Monkeypox)

 

87593 (Med Nec)

 

Respiratory virus panel

 

87631-87634 (Med Nec)

0098U – 0100U (Med Nec) (code deleted eff 3/31/21)

0115U (Med Nec)

0202U (Med Nec)

0151U (Med Nec) (code deleted eff 4/1/22)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)c

 

87635 (Med Nec)

 

Staphylococcus aureus

 

87640 (Med Nec)

 

Staphylococcus aureus, methicillin resistant

 

87641 (Med Nec)

 

Streptococcus group Ad

87650 (Med Nec)

87651 (Med Nec)

87652 (Inv)

Streptococcus group Be

 

87653 (Med Nec)

 

Trichomonas vaginalis

87660 (Med Nec)

87661 (Med Nec)

0353U (Med Nec)

 

Unlisted (infectious agent detection by nucleic acid, DNA or RNA, not otherwise specified)f

87797 (Inv)

87798 (Inv)

87799 (Inv)

Vaginal pathogen panel

 

0330U (Inv)

 

Zika Virus

 

87662 (Med Nec)

 

Refer to medical policy MP 359: Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease.

b For Candida species, culture for yeast remains the criterion standard for identifying and differentiating these organisms. Although sensitivity and specificity are higher for nucleic acid amplification tests (NAATs) than for standard testing methods, the CDC and other association guidelines do not recommend NAATs as first-line testing for Candida species. The CDC (2015) classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent; or mild to moderate; or, in non-immunocompromised women, as likely to be caused by C. albicans. A presumptive diagnosis can be made in the clinical care setting. However, for complicated infections, the CDC states that NAATs may be necessary to test for multiple Candida subspecies. Complicated vulvovaginal candidiasis is classified as being recurrent or severe; or, in women with uncontrolled diabetes, debilitation, or immunosuppression, as less likely to be caused by a C. albicans species.

c Use of NAAT for SARS-CoV-2 is for confirming Coronavirus Disease 2019 (COVID-19) diagnoses. This medical policy does not address antibody testing (serological IgG assays).

d Antibiotic sensitivity of streptococcus A cultures is frequently not performed for throat cultures. However, if an antibiotic sensitivity is considered, then the most efficient method of diagnosis would be a combined culture and antibiotic sensitivity.

e In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared to traditional culture techniques is the rapidity of results. This advantage suggests that the most appropriate use of the DNA probe technique is in the setting of impending labor, for which prompt results could permit the initiation of intrapartum antibiotic therapy.

f Testing submitted with these codes will be handled on a case by case basis. A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy.

Table Key:

Med Nec—meets medical criteria for coverage

Inv—does not meet medical criteria for coverage

Eff—effective


Effective for dates of service August 17, 2021 through July 26, 2022:

The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) may be considered medically necessary for the following microorganisms (see table at the end of this section for details on coding):

  • Bartonella henselae or quintana
  • Candida species
  • Chlamydia pneumoniae
  • Chlamydia trachomatis
  • Clostridium difficile
  • Enterococcus, vancomycin-resistant (e.g., enterococcus vanA, vanB)
  • Enterovirus
  • Gardnerella vaginalis
  • Gastrointestinal pathogen panels (GIPP)
  • Herpes simplex virus
  • Human papillomavirus (high risk type)
  • Influenza virus
  • Legionella pneumophila
  • Mycobacterium species
  • Mycobacterium tuberculosis
  • Mycobacterium avium intracellulare
  • Mycoplasma pneumoniae
  • Neisseria gonorrhoeae
  • Respiratory virus panel
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Staphylococcus aureus
  • Staphylococcus aureus, methicillin resistant
  • Streptococcus, group A
  • Streptococcus, group B
  • Trichomonas vaginalis
  • Zika virus

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) may be considered medically necessary for the following microorganisms:

  • Cytomegalovirus
  • Hepatitis B virus
  • Hepatitis C virus
  • HIV-1
  • HIV-2
  • Human herpes virus-6

The use of nucleic acid testing using a direct or amplified probe technique with or without quantification of viral load for microorganisms that are not included in the above list of microorganisms is considered investigational, including, but not limited to:

  • Hepatitis G virus
  • Human papillomavirus (low risk type)

The use of nucleic acid testing expanded panels using a direct or amplified probe technique with or without quantification of viral load is considered investigational for the following microorganisms, including, but not limited to:

  • Bacterial Vaginosis (BV) Panel
  • Infectious Disease (fungus and/or bacteria) Panel
  • Genitourinary Pathogen Panel

Multitarget polymerase chain reaction testing for the diagnosis of bacterial vaginosis is considered investigational.

CURRENT CODING:

CPT Codes:

The table below provides a list of CPT codes for various nucleic acid probes.

Table. CPT Codes for Nucleic Acid Probes

Pathogen

Direct Probe

Amplified Probe

Quantification

Bartonella henselae or quintana

 

87471 (Med Nec)

87472 (Inv)

0301U, 0302U (Inv)

Bacterial vaginosis

   

81513-81514 (Inv)

Blood stream pathogen identification

 

87154 (Med Nec)

 

Borrelia borgdorferia

87475 (Med Nec)

87476 (Med Nec)

 

Candida speciesb

87480 (Med Nec)

87481 (Med Nec)

0068U (Med Nec)

87482 (Inv)

Central Nervous System Pathogen Panel

 

87483 (Med Nec)

0323U (Inv)

Chlamydia pneumoniae

87485 (Med Nec)

87486 (Med Nec)

87487 (Inv)

Chlamydia trachomatis

87490 (Med Nec)

87491 (Med Nec)

87492 (Inv)

Clostridium difficile

87493 (Med Nec)

   

Cytomegalovirus

87495 (Med Nec)

87496 (Med Nec)

87497 (Med Nec)

Enterococcus, Vancomycin resistant (e.g., enterococcus van A, van B)

 

87500 (Med Nec)

 

Enterovirus

 

87498 (Med Nec)

 

Gardnerella vaginalis

87510 (Med Nec)

87511 (Med Nec)

87512 (Inv)

Gastrointestinal Pathogen Panel

 

87505-87507 (Med Nec)

0097U (Med Nec) (code deleted eff 4/1/22)

 

Genitourinary Pathogen Panel

 

0321U (Inv)

 

Hepatitis B

 

87516 (Med Nec)

87517 (Med Nec)

Hepatitis C

87520 (Med Nec)

87521 (Med Nec)

87522 (Med Nec)

Hepatitis G

87525 (Inv)

87526 (Inv)

87527 (Inv)

Herpes simplex virus

87528 (Med Nec)

87529 (Med Nec)

87530 (Inv)

Human Herpes virus-6

87531 (Med Nec)

87532 (Med Nec)

87533 (Med Nec)

Human Immunodeficiency Virus 1 (HIV-1)

87534 (Med Nec)

87535 (Med Nec)

87536 (Med Nec)

Human Immunodeficiency Virus 2 (HIV-2)

87537 (Med Nec)

87538 (Med Nec)

87539 (Med Nec)

Human Papillomavirus (HPV)

 

87623 (Inv) (low-risk type)

87624-87625 (Med Nec) (high-risk type)

 

Infectious Agent detection and identification

   

0112U (Inv)

Infectious disease panel (fungus and/or bacteria)

 

0140U-0142U (Inv)

 

Influenza virus

 

87501-87503 (Med Nec)

 

Legionella pneumophila

87540 (Med Nec)

87541 (Med Nec)

87542 (Inv)

Mycobacterium species

87550 (Med Nec)

87551 (Med Nec)

87552 (Inv)

Mycobacterium tuberculosis

87555 (Med Nec)

87556 (Med Nec)

87557 (Inv)

Mycobacterium avium intracellulare

87560 (Med Nec)

87561 (Med Nec)

87562 (Inv)

Mycoplasma pneumoniae

87580 (Med Nec)

87581 (Med Nec)

87582 (Inv)

Neisseria gonorrhoeae

87590 (Med Nec)

87591 (Med Nec)

87592 (Inv)

Respiratory virus panel

 

87631-87634 (Med Nec)

0098U – 0100U (Med Nec) (code deleted eff 3/31/21)

0115U (Med Nec)

0202U (Med Nec)

0151U (Med Nec) (code deleted eff 4/1/22)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)c

 

87635 (Med Nec)

 

Staphylococcus aureus

 

87640 (Med Nec)

 

Staphylococcus aureus, methicillin resistant

 

87641 (Med Nec)

 

Streptococcus group Ad

87650 (Med Nec)

87651 (Med Nec)

87652 (Inv)

Streptococcus group Be

 

87653 (Med Nec)

 

Trichomonas vaginalis

87660 (Med Nec)

87661 (Med Nec)

 

Unlisted (infectious agent detection by nucleic acid, DNA or RNA, not otherwise specified)f

87797 (Inv)

87798 (Inv)

87799 (Inv)

Vaginal pathogen panel

 

0330U (Inv)

 

Zika Virus

 

87662 (Med Nec)

 

Refer to medical policy MP 359: Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease.

b For Candida species, culture for yeast remains the criterion standard for identifying and differentiating these organisms. Although sensitivity and specificity are higher for nucleic acid amplification tests (NAATs) than for standard testing methods, the CDC and other association guidelines do not recommend NAATs as first-line testing for Candida species. The CDC (2015) classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent; or mild to moderate; or, in non-immunocompromised women, as likely to be caused by C. albicans. A presumptive diagnosis can be made in the clinical care setting. However, for complicated infections, the CDC states that NAATs may be necessary to test for multiple Candida subspecies. Complicated vulvovaginal candidiasis is classified as being recurrent or severe; or, in women with uncontrolled diabetes, debilitation, or immunosuppression, as less likely to be caused by a C. albicans species.

c Use of NAAT for SARS-CoV-2 is for confirming Coronavirus Disease 2019 (COVID-19) diagnoses. This medical policy does not address antibody testing (serological IgG assays).

d Antibiotic sensitivity of streptococcus A cultures is frequently not performed for throat cultures. However, if an antibiotic sensitivity is considered, then the most efficient method of diagnosis would be a combined culture and antibiotic sensitivity.

e In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared to traditional culture techniques is the rapidity of results. This advantage suggests that the most appropriate use of the DNA probe technique is in the setting of impending labor, for which prompt results could permit the initiation of intrapartum antibiotic therapy.

f Testing submitted with these codes will be handled on a case by case basis. A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy.

Table Key:

Med Nec—meets medical criteria for coverage

Inv—does not meet medical criteria for coverage

Eff—effective


Effective for dates of service April 1, 2020 through August 16, 2021:

The use of nucleic acid testing using a direct or amplified probe technique (without quantification of viral load) may be considered medically necessary for the following microorganisms (see Table at the end of this section for details on coding):

  • Bartonella henselae or quintana
  • Candida species
  • Chlamydia trachomatis
  • Clostridium difficile
  • Enterococcus, vancomycin-resistant (e.g., enterococcus vanA, vanB)
  • Enterovirus
  • Gardnerella vaginalis
  • Herpes simplex virus
  • Human papillomavirus
  • Influenza virus
  • Legionella pneumophila
  • Mycobacterium species
  • Mycobacterium tuberculosis
  • Mycobacterium avium intracellulare
  • Mycoplasma pneumoniae
  • Neisseria gonorrhoeae
  • Respiratory virus panel
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
  • Staphylococcus aureus
  • Staphylococcus aureus, methicillin resistant
  • Streptococcus, group A
  • Streptococcus, group B
  • Trichomonas vaginalis
  • Zika virus

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) may be considered medically necessary for the following microorganisms:

  • Cytomegalovirus
  • Hepatitis B virus
  • Hepatitis C virus
  • HIV-1
  • HIV-2
  • Human herpes virus-6

The use of nucleic acid testing with quantification of viral load for microorganisms that are not included in the list of microorganisms is considered investigational.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) is considered investigational for the following microorganisms including but not limited to:

  • Hepatitis G virus
  • Human papillomavirus (low risk panel)
  • Gastrointestinal Pathogen Panel (GIPP)

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) may be considered medically necessary for gastrointestinal pathogen panels (GIPP) for the following:

  • Individuals with acute diarrhea* with moderate-to-severe symptoms (such as fever, dysentery, severe dehydration); OR
  • Individuals with community-acquired diarrhea that persists for more than seven days, or individuals with travel-associated diarrhea of uncertain etiology; OR
  • Immunocompromised individuals with acute diarrhea*

*Gastrointestinal Pathogen Panel testing is limited to the minimum number of targets needed for therapeutic decision making.

The use of nucleic acid testing using a direct or amplified probe technique (with or without quantification of viral load) is considered investigational for gastrointestinal pathogen panels (GIPP) for the following:

  • Immunocompetent individuals with mild diarrhea, particularly of less than or equal to seven (7) days’ duration; OR
  • Individuals in whom the clinical presentation of acute diarrhea* suggests a specific infectious etiology, unless first-line laboratory testing should fail to detect the suspected organism, and there is still a high clinical suspicion of infectious etiology; OR
  • Individuals with chronic diarrhea*

*Diarrhea defined:

Acute diarrhea: 0-2 week’s duration

Persistent diarrhea: 2-4 week's duration

Chronic diarrhea: > 4 week's duration

Bacterial Vaginosis (BV)

Multitarget polymerase chain reaction testing for the diagnosis of bacterial vaginosis is considered investigational. (There is no single CPT Code for BV testing)

CURRENT CODING:

CPT Codes:

The table below provides a list of CPT codes for various nucleic acid probes.

Table. CPT Codes for Nucleic Acid Probes

Pathogen

Direct Probe

Amplified Probe

Quantification

Bartonella henselae or quintana

 

87471 (Med Nec)

87472 (Inv)

Borrelia borgdorferia

87475 (Med Nec)

87476 (Med Nec)

 

Candida speciesb

87480 (Med Nec)

87481 (Med Nec)

0068U (Med Nec)

87482 (Inv)

Central Nervous System Pathogen Panel

 

87483 (Med Nec)

 

Chlamydia pneumoniae

87485 (Med Nec)

87486 (Med Nec)

87487 (Inv)

Chlamydia trachomatis

87490 (Med Nec)

87491 (Med Nec)

87492 (Inv)

Clostridium difficile

87493 (Med Nec)

   

Cytomegalovirus

87495 (Med Nec)

87496 (Med Nec)

87497 (Med Nec)

Enterococcus, Vancomycin resistant (e.g., enterococcus van A, van B)

 

87500 (Med Nec)

 

Enterovirus

 

87498 (Med Nec)

 

Gardnerella vaginalis

87510 (Med Nec)

87511 (Med Nec)

87512 (Inv)

Gastrointestinal Pathogen Panel

 

87505-87507 (Med Nec)

0097U (Med Nec)

 

Hepatitis B

 

87516 (Med Nec)

87517 (Med Nec)

Hepatitis C

87520 (Med Nec)

87521 (Med Nec)

87522 (Med Nec)

Hepatitis G

87525 (Inv)

87526 (Inv)

87527 (Inv)

Herpes simplex virus

87528 (Med Nec)

87529 (Med Nec)

87530 (Inv)

Human Herpes virus-6

87531 (Med Nec)

87532 (Med Nec)

87533 (Med Nec)

Human Immunodeficiency Virus 1 (HIV-1)

87534 (Med Nec)

87535 (Med Nec)

87536 (Med Nec)

Human Immunodeficiency Virus 2 (HIV-2)

87537 (Med Nec)

87538 (Med Nec)

87539 (Med Nec)

Human Papillomavirus (HPV)

 

87623(Inv)

87624-87625 (Med Nec)

 

Infectious Agent detection and identification

   

0112U ((Inv)

Infectious disease

 

0140U-0142U (Inv)

81513-81514  (Inv)

Influenza virus

87501 (Med Nec)

87502 (Med Nec)

87503 (Med Nec)

Legionella pneumophila

87540 (Med Nec)

87541 (Med Nec)

87542 (Inv)

Mycobacterium species

87550 (Med Nec)

87551(Med Nec)

87552 (Inv)

Mycobacterium tuberculosis

87555 (Med Nec)

87556 (Med Nec)

87557 (Inv)

Mycobacterium avium intracellulare

87560 (Med Nec)

87561 (Med Nec)

87562 (Inv)

Mycoplasma pneumoniae

87580 (Med Nec)

87581 (Med Nec)

87582 (Inv)

Neisseria gonorrhoeae

87590 (Med Nec)

87591 (Med Nec)

87592 (Inv)

Respiratory virus panel

 

87631-87634 (Med Nec)

0098U – 0100U (code deleted eff 03/31/21) (Med Nec)

0115U (Med Nec)

0202U (Med Nec)

0151U (Med Nec)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)c

 

87635 (Med Nec)

 

Staphylococcus aureus

 

87640 (Med Nec)

 

Staphylococcus aureus, methicillin resistant

 

87641 (Med Nec)

 

Streptococcus group Ad

87650 (Med Nec)

87651 (Med Nec)

87652 (Inv)

Streptococcus group Be

 

87653 (Med Nec)

 

Trichomonas vaginalis

87660 (Med Nec)

87661 (Med Nec)

 

Unlisted (infectious agent detection by nucleic acid (DNA or RNA, not otherwise specified)f

87797 (Inv)

87798 (Inv)

87799 (Inv)

Zika Virus

 

87662 (Med Nec)

 

a Refer to medical policy specific to Intravenous Antibiotic Therapy and Associated Diagnostic Testing for Lyme Disease.

For uncomplicated infections, testing for only one candida species, C albicans, may be considered medically necessary. For complicated infections, testing for multiple candida subspecies may be considered medically necessary. The Centers for Disease Control and Prevention classifies uncomplicated vulvovaginal candidiasis as being sporadic or infrequent or mild to moderate or likely to be C. albicans or in non-immunocompromised women. Complicated vulvovaginal candidiasis is classified as being recurrent or severe or not a C. albicans species or in women with uncontrolled diabetes, debilitation or immunosuppression.

c Use of NAAT for SARS-CoV-2 is for confirming Coronavirus Disease 2019 (COVID-19) diagnoses. This medical policy does not address antibody testing (serological IgG assays).

d Antibiotic sensitivity of streptococcus A cultures is frequently not performed for throat cultures. However, if an antibiotic sensitivity is considered, then the most efficient method of diagnosis would be a combined culture and antibiotic sensitivity.

e In the evaluation of group B streptococcus, the primary advantage of a DNA probe technique compared to traditional culture techniques is the rapidity of results. This advantage suggests that the most appropriate use of the DNA probe technique is in the setting of impending labor, for which prompt results could permit the initiation of intrapartum antibiotic therapy.

f Testing submitted with these codes will be handled on a case by case basis. A discussion of every infectious agent that might be detected with a probe technique is beyond the scope of this policy.

Table Key:

Med Nec—meets medical criteria for coverage

Inv—does not meet medical criteria for coverage

Eff—effective

DESCRIPTION OF PROCEDURE OR SERVICE:

Nucleic Acid Probes

Nucleic acid probes are available for the identification of a wide variety of microorganisms. Nucleic acid probes can also be used to quantitate the number of microorganisms present. This technology offers advantages over standard techniques when rapid identification is clinically important, microbial identification using standard culture is difficult or impossible, and/or treatment decisions are based on quantitative results.

The availability of nucleic acid probes has permitted the rapid direct identification of microorganism DNA or RNA. Amplification techniques result in exponential increases in copy numbers of a targeted strand of microorganism-specific DNA. The most used amplification technique is polymerase chain reaction (PCR) or reverse transcriptase PCR. In addition to PCR, other nucleic acid amplification techniques have been developed, such as transcription-mediated amplification, loop-mediated isothermal DNA amplification, strand displacement amplification, nucleic acid sequence-based amplification, and branched-chain DNA signal amplification. After amplification, target DNA can be readily detected using a variety of techniques. The amplified product can also be quantified to assess how many microorganisms are present. Quantification of the number of nucleic acids permits serial assessments of response to treatment; the most common clinical application of quantification is the serial measurement of HIV RNA (called viral load).

The direct probe technique, amplified probe technique, and probe with quantification methods vary based on the degree to which the nucleic acid is amplified and the method for measurement of the signal. The direct probe technique refers to detection methods in which nucleic acids are detected without an initial amplification step. The amplified probe technique refers to detection methods in which either target, probe, or signal amplification is used to improve the sensitivity of the assay over direct probe techniques, without quantification of nucleic acid amounts.

  • Target amplification methods include PCR (including PCR using specific probes, nested or multiplex PCR), nucleic acid-based sequence amplification, transcription-mediated amplification, and strand displacement amplification. Nucleic acid-based sequence amplification and transcription-mediated amplification involve amplification of an RNA (rather than a DNA) target.
  • Probe amplification methods include ligase chain reaction.
  • Signal amplification methods include branched DNA (bDNA) probes and hybrid capture methods using an anti-DNA/RNA hybrid antibody.

The probe with quantification techniques refers to quantitative PCR or real-time PCR methods that use a reporter at each stage of the PCR to generate absolute or relative amounts of a known nucleic acid sequence in the original sample. These methods may use DNA specific dyes (ethidium bromide or SYBR green), hybridization probes (cleavage-based [TaqMan] or displaceable), or primer incorporated probes.

Direct assays will generally have lower sensitivity than amplified probes. In practice, most commercially available probes are amplified, with a few exceptions. For this evidence review, indications for direct and/or amplified probes without quantification are considered together, while indications for a probe with quantification are considered separately.

Classically, identification of microorganisms relies either on the culture of body fluids or tissues or identification of antigens, using a variety of techniques including direct fluorescent antibody technique and qualitative or quantitative immunoassays. These techniques are problematic when the microorganism exists in very small numbers or is technically difficult to culture. Indirect identification of microorganisms by immunoassays for specific antibodies reactive with the microorganism is limited by difficulties in distinguishing between past exposure and current infection.

Potential reasons for a nucleic acid probe to be associated with improved clinical outcomes compared with standard detection techniques include the following (note: in all cases, for there to be clinical utility, making a diagnosis should be associated with changes in clinical management, which could include initiation of effective treatment, discontinuation of other therapies, or avoidance of invasive testing.):

  • Significantly improved speed and/or efficiency in making a diagnosis.
  • Improved likelihood of obtaining any diagnosis in cases where standard culture is difficult. Potential reasons for difficulty in obtaining standard culture include low numbers of the organisms (e.g., HIV), fastidious or lengthy culture requirements (e.g., Mycobacteria, Chlamydia, Neisseria species), or difficulty in collecting an appropriate sample (e.g., herpes simplex encephalitis).
  • There is no way to definitively make a diagnosis without nucleic acid testing.
  • The use of nucleic acid probe testing provides qualitatively different information than that available from standard cultures, such as information regarding disease prognosis or response to treatment. These include cases where quantification of viral load provides prognostic information or is used to measure response to therapy.

The risks of nucleic acid testing include false-positive and false-negative results; inaccurate identification of pathogens by the device, inaccurate interpretation of test results, or incorrect operation of the instrument.

  • False-positive results can lead to unnecessary treatment, with its associated toxicities and side effects, including allergic reaction. In addition, true diagnosis and treatment could be delayed or missed altogether.
  • False-negative results could delay diagnosis and initiation of proper treatment.
  • It is possible that these risks can be mitigated by the use of a panel of selected pathogens indicated by the clinical differential diagnosis while definitive culture results are pending.

Bacterial Vaginosis

Bacterial vaginosis (BV) is a common medical condition resulting from an imbalance in the normal vaginal flora. Although the identification of Gardnerella vaginalis has traditionally been associated with BV, there is no single etiologic agent. Most cases are asymptomatic, and most symptomatic cases can be diagnosed using clinical and microscopic evaluation. Multitarget polymerase chain reaction (PCR) testing is proposed as an alternative to currently available laboratory tests to diagnose BV. This test may improve outcomes if it is a more accurate and reliable method to diagnose BV.

Vaginal culture is not an appropriate diagnostic method to identify BV because BV is not caused by the presence of a particular bacterial species.

Various commercial tests provide rapid and accurate pH evaluation and amine detection. For example, automated devices that measure the volatile gases produced from vaginal samples and a colorimetric pH test are commercially available.

Nucleic acid probes of DNA fragments are available to detect and quantify specific bacteria in vaginal fluid samples. Polymerase chain reaction (PCR) methods extract and amplify the DNA fragments using either universal or specific primers. The result can be qualitative (to assess whether a specific microorganism is present) or quantitative (to assess how many microorganisms are present). The technology can be used to measure multiple organisms (e.g., those known to be associated with BV) at the same time and is commercially available as multitarget PCR testing.

Proposed Multitarget PCR Tests for Bacterial Vaginosis

The SureSwab Total (Quest Diagnostics) test involves obtaining vaginal swab specimens, extracting total DNA, and quantitating the four types of bacteria using PCR. Results are reported as log cells per milliliter for each organism and concentrations of all Lactobacilli species are reported together then classified into one of the following three categories: not supportive, equivocal, and supportive.

A classification of not supportive of BV diagnosis is based on:

  • The presence of Lactobacillus species, G. vaginalis levels <6.0 log cells/mL, and absence of Atopobium vaginae and Megasphaera species; or
  • The absence of Lactobacillus species, G. vaginalis levels <6.0 log cells/mL, and absence of A. vaginae and Megasphaera species; or
  • The absence of all targeted organisms.

A classification of equivocal is based on:

  • The presence of Lactobacillus species, plus G. vaginalis at least 6.0 log cells/mL, and/or presence of A. vaginae and/or Megasphaera species.

A classification of supportive of BV diagnosis is based on the absence of Lactobacillus species, and presence of G. vaginalis levels of at least 6.0 log cells/mL, and presence of A. vaginae and/or Megasphaera species.

Another product, the BD Max (Becton, Dickinson), tests for markers of BV and vaginitis. The test uses a similar process to that described for SureSwab. Vaginal swab specimens are collected, DNA is extracted, and real-time PCR is used to quantitate targeted organisms. Results of BV marker tests are not reported for individual organisms. Instead, qualitative BV results are reported as positive or negative for BV based on the relative quantity of the various organisms. The Aptima BV Assay was cleared by the FDA with the BD Max as the predicate device. The Aptima assay is a nucleic acid amplification test (NAAT) for detection and quantitation of ribosomal RNA.

Medical Diagnostics Laboratory offers a Bacterial Vaginosis Panel. Markers are assessed using real-time PCR and Lactobacillus is profiled using quantitative PCR. GenPath Diagnostics also offers a bacterial vaginosis test.

The NuSwab® Select BV test (Laboratory Corporation of America) uses semi quantitative PCR analysis of three predictive marker organisms of vaginal dysbiosis to generate a total score that is associated with the presence or absence of BV. In this test system, samples with a total score of zero to one are considered negative for BV, samples with a score of three to six are positive for BV, and samples with a score of two are indeterminate for BV.

Several of the manufacturers of the BV tests also have extensions that include other causes of vaginitis such as Trichomonas vaginalis and Candidiasis species.

KEY POINTS:

The most recent literature update for this evidence review was performed through May 10, 2022.

Summary of Evidence

For individuals who have signs and/or symptoms of meningitis and/or encephalitis who receive a nucleic acid-based central nervous system pathogen panel, the evidence includes a systematic review and a pivotal prospective study. Access to a rapid method that can simultaneously test for multiple pathogens may lead to the faster initiation of more effective treatment and conservation of cerebrospinal fluid. The available central nervous system panel is highly specific for the included organisms. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who receive a nucleic acid-based gastrointestinal pathogen panel testing (GIPP), the evidence includes prospective and retrospective evaluations of the tests’ sensitivity and specificity. The available evidence suggests that gastrointestinal pathogen panels are likely to identify both bacterial and viral pathogens with high sensitivity, compared with standard methods. Access to a rapid method for etiologic diagnosis of gastrointestinal infections may lead to more effective early treatment and infection-control measures. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have signs and/or symptoms of respiratory infection who receive a nucleic acid-based respiratory pathogen panel, the evidence includes a systematic review and two randomized controlled trials (RCTs). The systematic review reported that all three reviewed multiplex polymerase chain reaction systems were highly accurate. One RCT and one quasi-RCT evaluated utility of a respiratory panel and found benefits in time-to-treat and length of hospital stay. In addition, one sub analysis found fewer antibiotics being prescribed for patients diagnosed with the panel. The panel did not significantly affect duration of antibiotic use, readmission, or mortality rates. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have signs or symptoms of BV who receive multitarget PCR testing, the evidence includes several prospective studies on technical performance and diagnostic accuracy. The relevant outcomes are test validity, symptoms, and change in disease status. Several studies have evaluated the diagnostic accuracy of multitarget PCR tests for BV, including five studies evaluating commercially available tests. The studies found sensitivities between 84% and 95% and specificities between 85% and 97% compared with standard methods of diagnosis. Most studies used a combination of the Amsel criteria and Nugent scoring as the reference standard. There is a lack of direct evidence on the clinical utility of PCR testing for BV (i.e., studies showing that testing leads to better patient management decisions and/or better health outcomes than current approaches). Moreover, a chain of evidence does not currently support multitarget testing because most symptomatic women can be diagnosed with a standard workup. The evidence is insufficient to determine that the technology results in an improvement in the net health outcomes.

For other nucleic acid probes addressed in this review, the tests’ clinical utility was evaluated based on whether there is demonstrated clinical validity, along with either direct evidence of improved outcomes or a chain of evidence indicating that changes in management leading to improved outcomes are likely to occur with testing.

Practice Guidelines and Position Statements

Numerous guidelines have been identified concerning the use of NAATs for the diagnosis of the pathogens discussed in this review. Inclusion of information below does not imply coverage/non-coverage.

The table below provides an index of NAAT recommendation by virus/infection.

Table. Index of NAAT Recommendations by Virus/Infection

Microorganism

Guidelines Recommending the Use of NAATs (Location)

Guidelines Not Recommending the Use of NAATsa (Location)

Bartonella hensalae

NIH (2.1.1), IDSA (3.1), AAP (5.1)

NA

Candida species

AAP (5.1), CDC (1.5.1)b

IDSA (3.1, 3. 6)

CNS pathogen panel

IDSA (3.2, 3.3)

NA

Chlamydia pneumoniae

AAP (5.1), CDC (1.5.3), IDSA (3.1c)

NA

Chlamydia trachomatis

AAP (5.1), CDC (1.5.2c, 1.6c), IDSA (3.1),

NA

Clostridioides (Clostridium) difficile

NIH (2.1.2), AAP (5.1)

IDSA (3.1, 3.4)

Cytomegalovirus

CDC (1.1), NIH (2.1.3), IDSA (3.1c , 3.3)

AAP (5.1)

Enterovirus

IDSA (3.1), AAP (5.1)

NA

Gardnerella vaginalis

AAP (5.1), CDC (1.5.4)

IDSA (3.1)

GI pathogen panel

CDC (1.4c), IDSA (3.5), ACG (6.1)

NA

Hepatitis B

NIH (2.1.4), IDSA (3.1), AAP (5.1)

NA

Hepatitis C

CDC (1.5.5c), NIH (2.1.5), IDSA (3.1), AAP (5.1)

NA

Herpes simplex virus

CDC (1.5.6c), NIH (2.1.6), IDSA (3.1c, 3.3), AAP (5.1)

NA

Human herpesvirus 6

IDSA (3.1c, 3.3)

AAP (5.1)

Human papillomavirus

CDC (1.5.8c), AAP (5.1)

NA

HIV 1

CDC (1.5.7c), IDSA (3.1), AAP (5.1)

NA

Influenza virus

IDSA (3.1c), AAP (5.1)

NA

Legionella pneumophila

IDSA (3.1), AAP (5.1)

NA

Meningitis

NA

IDSA (3.2)

Mycobacteria species

CDC (1. 7), NIH (2.1.7), IDSA (3.1, 3.3)

AAP (5.1)

Mycoplasma pneumoniae

CDC (1.2c), IDSA (3.3), AAP (5.1)

NA

Neisseria gonorrhoeae

CDC (1.6c), IDSA (3.1), AAP (5.1)

NA

Respiratory panel

None Identified

NA

SARS-CoV-2

IDSA (3. 7)

NA

Staphylococcus aureus

IDSA (3.1), AAP (5.1)

NA

Streptococcus, group A

IDSA (3.1)

AAP (5.1)

Streptococcus, group B

AAP (5.2), ASM (7.1)

IDSA (3.1), AAP (5.1)

Trichomonas vaginalis

CDC (1.5.9), IDSA (3.1)c, AAP (5.1)

NA

Vancomycin-resistant Enterococcus

AST (4.1)

IDSA (3.1), AAP (5.1)

Zika virus

CDC (1.3), IDSA (3.1), AAP (5.1)

NA

AAP: American Academy of Pediatrics; ACG: American College of Gastroenterology; ASM: American Society for Microbiology; AST: American Society of Transplantation; CDC: Centers for Disease Control and Prevention; CNS: central nervous system; GI: gastrointestinal; HIV: human immunodeficiency virus; IDSA: Infectious Disease Society of America; NA: not applicable (none found); NAAT: nucleic acid amplification test; NIH: National Institutes of Health; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2.

a Guidelines Not Recommending includes not only guidelines that recommend against NAATs but also those that were neutral on the use of NAATs.

b CDC recommends culture for first-line identification of Candida species; it recommends NAAT for complicated infections and for second-line diagnosis.

c Indicates guidelines in which the issuing body specifically recommends that U.S. Food and Drug Administration (FDA)-cleared NAATs be used.

American Academy of Pediatrics

The thirty-second edition of the American Academy of Pediatrics (AAP) Red Book (2021) describes the diagnostic and treatment options for many infectious diseases in the pediatric population. Their recommendations for appropriate diagnostic tests for the viruses and infections discussed in this policy are detailed in the table below.

Table. Red Book Diagnostic Test Recommendations for the Pediatric Population

Infection

Diagnostic Test Recommendation

Bartonella henselae

EIA

IFA

NAAT (PCR)

Candida species

Clinical evaluation microscopy

PNA FISH probes and PCR assays developed for rapid detection directly from positive blood cultures

Chlamydia pneumoniae

NAATs (PCR) are the preferred method for diagnosis of acute infection

Serologic antigen test is an option, but is technically complex and interpretation is subjective

Chlamydia trachomatis

NAATs are recommended for C trachomatis urogenital infections and in post pubescent individuals. They are not recommended for diagnosing C trachomatis conjunctivitis or pneumonia or in the evaluation of prepubescent children for possible sexual assault.

Clostridioides (Clostridium) difficile

NAATs detect genes responsible for the production of toxins A and B, rather than free toxins A and B in the stool, which are detected by EIA

NAAT could be considered alone if a policy in place to screen symptoms; if no policy in place, multi-step algorithms involving EIA, GDH, NAAT plus toxin is recommended

Coronaviruses (including SARS-CoV-2 and MERS-CoV)

RT-PCR

Direct antigen testing

Cytomegalovirus

Saliva PCR is the preferred diagnostic tool for screening.

Enterovirus

RT-PCR and culture from a variety of specimens

Gardnerella vaginalis

Microscopy

Numerous NAATs have been recommended when microscopy is unavailable

Hepatitis B

Serologic antigen tests

NAATs

Hepatitis C

IgG antibody enzyme immunoassays

NAATs

Herpes simplex virus

Cell culture

NAATs- diagnostic method of choice for neonates with CNS infections, older children, and adults with HSE

Human herpesvirus 6

Few developed assays are available commercially and do not differentiate between new, past, and reactivated infection. Therefore, these tests “have limited utility in clinical practice:”

Serologic tests;

PCR- the assays are not sensitive in younger children.

HIV 1

HIV DNA PCR or RNA PCR-preferred test to diagnose HIV infection in infants and children younger than 18mo; highly sensitive and specific by 2 weeks of age and available

Human papillomavirus

“Detection of HPV infection is based on detection of viral nucleic acid.”

Influenza virus

“RT-PCR, viral culture tests, and rapid influenza molecular assays are available options for testing; optimal choice of influenza test depends on the clinical setting.”

Legionella pneumophila

BCYE media

Legionella antigen in urine

Direct IFA

Genus-specific PCR reaction-based assays

Meningitis

Cultures of blood and CSF

NAATs- “useful in patients who receive antimicrobial therapy before cultures are obtained.”

Mycobacteria species

M tuberculosis disease:

Chest radiography and physical examination

Several NAATs are cleared for rapid detection of M tuberculosis, but expert consultation is recommended for interpretation of results.

NTM: “definite diagnosis of NTM disease requires isolation of the organism.”

Mycoplasma pneumoniae

“PCR tests for M pneumonia are available commercially and increasing replacing other tests, because PCR tests performed on respiratory tract specimens have sensitivity and specifically between 80% and 100%, yield positive results earlier in the course of illness than serologic tests, and are rapid.”

Neisseria gonorrhoeae

“NAATs are far superior in overall performance compared with other N gonorrhoeae culture and nonculture diagnostic methods to test genital and nongenital specimens, but performance varies by NAAT type.”

Staphylococcus aureus

“NAATS are approved for detection and identification of S aureus, including MRSA, in positive blood cultures.”

Streptococcus, group A

“Children with pharyngitis and obvious viral symptoms should not be tested or treated for group A streptococcal infection. Laboratory confirmation is required for cases in children without viral symptoms… culture on sheep blood agar can confirm group A streptococcal infection.”

Streptococcus, group B

“Gram-positive cocci in pairs or short chains from a normally sterile body fluid provides presumptive evidence of infection.”

Trichomonas vaginalis

Microscopy

NAATs are “the most sensitive mean of diagnosing T vaginalis infection and is encouraged for detection in females and males.”

Vancomycin-resistant Enterococcus

"Selective agars are available for screening of vancomycin-resistant enterococcus from stool specimens. Molecular assays are available for direct detection of vanA and vanB genes from rectal and blood specimens to identify vancomycin-resistant enterocci"

Zika virus

NAATs

Trioplex real-time PCR assay

Serologic testing

 

BCYE: buffered charcoal yeast extract; CNS: central nervous system; CSF: cerebrospinal fluid; DNA: deoxyribonucleic acid; EIA: enzyme immunoassay; FDA: Food and Drug Administration; GDH: glutamate dehydrogenase; HIV: human immunodeficiency virus; HPV: human papillomavirus; HSE: herpes simplex encephalitis; IFA: indirect fluorescent antibody; MERS-CoV: Middle East respiratory syndrome coronavirus; MSRA: methicillin-resistant Staphylococcus aureus; NAAT: nucleic acid amplification test; NTM: nontuberculous mycobacteria; PCR: polymerase chain reaction; PNA FISH: peptide nucleic acid fluorescent in situ hybridization; RNA: ribonucleic acid; RT: reverse transcriptase; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

In 2019, the AAP published guidelines on managing infants at risk for group B streptococcus (GBS). It recommends antenatal vaginal-rectal culture performed by using a broth enrichment “followed by GBS identification by using traditional microbiologic methods or by NAAT-based methods.” However, point-of-care NAAT-based screening should not be the primary method of determining maternal colonization status due to reported variable sensitivity as compared with traditional culture, as well as “because most NAAT-based testing cannot be used to determine the antibiotic susceptibility of colonizing GBS isolates among women with a penicillin allergy.”

American College of Gastroenterology

In 2016, the American College of Gastroenterology published clinical guidelines on the diagnosis, treatment, and prevention of acute diarrheal infections in adults. It recommended that, given that “traditional methods of diagnosis (bacterial culture, microscopy with and without special stains and immunofluorescence, and antigen testing) fail to reveal the etiology of the majority of cases of acute diarrheal infection, … the use of FDA-approved culture-independent methods of diagnosis can be recommended at least as an adjunct to traditional methods. (Strong recommendation, low level of evidence).” These are described in the rationale as multiplex molecular testing.

American College of Obstetricians and Gynecologists

For Bacterial Vaginosis: Published in 2012 and reaffirmed in 2018, the American College of Obstetricians and Gynecologists (ACOG) has produced a Practice Bulletin on the prediction of preterm birth. The Bulletin stated that BV testing is not recommended as a screening strategy in asymptomatic pregnant women at increased risk of preterm birth.

Published in 2020, the ACOG has issued a Practice Bulletin on vaginitis in nonpregnant patients. The Bulletin made the following recommendations on the initial evaluation of patients with symptoms of vaginitis, citing CDC guidelines:

"A complete medical history, physical examination of the vulva and vagina, and clinical testing of vaginal discharge (i.e., pH testing, a potassium hydroxide "whiff test," and microscopy) are recommended for the initial evaluation of patients with vaginitis symptoms."

The Bulletin noted that single-swab multiplex PCR testing "may be a promising alternative to microscopy," but that its clinical utility is still under evaluation.

American Society for Microbiology

In 2020, the American Society for Microbiology updated the 2010 guidelines on detecting and identifying GBS that were originally published by the CDC, with plans to continue updating regularly. The most recent update took place July 2021. The guidelines state that "intrapartum NAAT without enrichment has an unacceptably high false negative rate...As such we do not recommend the use of intrapartum NAAT without enrichment to rule out the need for prophylaxis." All GBS screening specimens should be incubated in selective enrichment broth prior to agar media plating or NAAT. "Nucleic acid amplification-based identification of GBS from enrichment broth is acceptable" for GBS screening, "but not sufficient for all patients" due to high false-negative rates.

American Society of Transplantation

In 2019, The American Society of Transplantation Infectious Diseases Community of Practice published guidelines which addressed vancomycin-resistant enterococci infections in solid organ transplant patients. The guidelines noted the cost-effectiveness and accuracy of “emerging molecular diagnostics for VRE colonization, including multiplexed PCR performed after culture on selective media,” compared with culture alone.

Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) has published multiple recommendations and statements regarding the use of NAATs to diagnose the viruses and infections discussed in this evidence review since 2009.

  1. The CDC published guidance for laboratory testing for cytomegalovirus (CMV), the guideline stated that the standard laboratory test for congenital CMV is PCR on saliva, with confirmation via urine test to avoid false-positive results from ingesting breast milk from CMV seropositive mothers. Serologic tests were recommended for person >12 months of age.
  2. The CDC published diagnostic methods for mycoplasma pneumoniae. They cited NAAT as a method of diagnosis, along with culture or serology.
  3. The CDC published updated guidelines on Zika virus testing. Routine testing for Zika virus in asymptomatic pregnant patients is not recommended, but NAAT testing may still be considered for asymptomatic pregnant women with recent travel to an area with risk of Zika outside the U.S. and its territories. Symptomatic pregnant patients should receive NAAT testing if they have recently traveled to areas with a risk of Zika virus or if they have had sex with someone who lives in or recently traveled to areas with risk of Zika virus. If a pregnant woman (with risk of Zika virus exposure) has a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection, Zika virus NAAT and IgM testing should be performed on maternal serum and NAAT on maternal urine. If amniocentesis is being performed as part of clinical care, Zika virus NAAT testing of amniocentesis specimens should also be performed.
  4. In 2017, the CDC updated its guidelines on norovirus gastroenteritis outbreak management and disease prevention. Real-time reverse transcription-PCR assays, specifically, TaqMan-based real-time assays, which can contain multiple probes, is considered the effective laboratory diagnostic protocol for testing suspected cases of viral gastroenteritis.
  5. In 2015, the CDC made recommendations were made for the use of NAATs in diagnosing numerous sexually transmitted infections. These recommendations were most recently updates in 2021, with the publication of new guidelines and the following recommendations:
  • For Candida species: "The majority of PCR tests for yeast are not FDA [U.S. Food and Drug Administration] cleared, and providers who use these tests should be familiar with the performance characteristics of the specific test used."
  • For Gonococcal Infections:
    • "Culture, NAAT, and POC [point of care] NAAT, such as GeneXpert (Cepheid), are available for detecting genitourinary infection with N. gonorrhoeae"
    • "NAATs and POC NAATs allow for the widest variety of FDA-cleared specimen types, including endocervical and vaginal swabs and urine for women, urethral swabs and urine for men, and rectal swabs and pharyngeal swabs for men and women. However, product inserts for each NAAT manufacturer should be consulted carefully because collection methods and specimen types vary."
  • For Chlamydial Infection: "NAATs are the most sensitive tests for these specimens and are the recommended test for detecting C. trachomatis infection. NAATs that are FDA cleared for use with vaginal swab specimens can be collected by a clinician or patient in a clinical setting. Patient collected vaginal swab specimens are equivalent in sensitivity and specificity to those collected by a clinician using NAATs, and this screening strategy is highly acceptable among women. Optimal urogenital specimen types for chlamydia screening by using NAAT include first catch urine (for men) and vaginal swabs (for women). Recent studies have demonstrated that among men, NAAT performance on self-collected meatal swabs is comparable to patient-collected urine or provider-collected urethral swabs."
  • For Gardnerella vaginalis: "Multiple BV [bacterial vaginosis] NAATs are available for BV diagnosis among symptomatic women. These tests are based on detection of specific bacterial nucleic acids and have high sensitivity and specificity for BV (i.e., G. vaginalis, A. vaginae, BVAB2, or Megasphaera type 1) and certain lactobacilli (i.e., Lactobacillus crispatus, Lactobacillus jensenii, and Lactobacillus gasseri)...Five quantitative multiplex PCR assays are available...Two of these assays are FDA cleared (BD MaxVaginal Panel and Aptima BV), and the other three are laboratory-developed tests."
  • For hepatitis C infection (HCV): In addition, “testing for HCV infection should include use of an FDA-cleared test for antibody to HCV…followed by NAAT to detect HCV RNA for those with a positive antibody result.” Persons with HIV infection with low CD4+ T-cell count might require further testing by NAAT because of the potential for a false-negative antibody assay.”
  • For diseases characterized by genital, anal, or perianal ulcers (e.g., herpes simplex virus [HSV], syphilis):
    • "Specific evaluation of genital, anal, or perianal ulcers includes syphilis serology tests and darkfield examination from lesion exudate or tissue, or NAAT if available; NAAT or culture for genital herpes type 1 or 2; and serologic testing for type-specific HSV antibody. In settings where chancroid is prevalent, a NAAT or culture for Haemophilus ducreyi should be performed;"
    • "PCR is also the test of choice for diagnosing HSV infections affecting the central nervous system (CNS) and systemic infections (e.g., meningitis, encephalitis, and neonatal herpes). HSV PCR of the blood should not be performed to diagnose genital herpes infection, except in cases in which concern exists for disseminated infection (e.g., hepatitis)."
  • For Human immunodeficiency virus 1 (HIV-1): The use of NAAT is not mentioned; serologic tests are recommended for detecting antibodies against HIV-1 and by virologic tests that detect HIV antigens or RNA.
  • For human papillomavirus (HPV):
    • There are several FDA-cleared HPV tests that detect viral nucleic acid or messenger RNA; however, there are currently no algorithms for HPV 16/18/45 testing in the clinical guidelines;
    • Testing for nononcogenic HPV (types 6 and 11) is not recommended; and
    • “HPV assays should be FDA-cleared and used only for the appropriate indications” and should not be performed if the patient is “deciding whether to vaccinate against HPV;” when “providing care to persons with genital warts or their partners;” when “testing persons aged <25 years as part of routine cervical cancer screening;” or when “testing oral or anal specimens.”
  • For Trichomonas vaginalis:
    • NAAT is recommended for detecting T vaginalis in women due to its high sensitivity and specificity. Multiple assays are FDA-cleared to detect T vaginalis from vaginal, endocervical, or urine specimens for women.
    • Although there is not a currently FDA-cleared assay test available for use in men, assays "...should be internally validated in accordance with CLIA [Clinical Laboratory Improvement Amendments] regulations before use with urine or urethral swabs from men."
  • In 2014, the CDC published recommendations regarding the laboratory-based detection of C. trachomatis and N. gonorrhoeae infections. It stated:
    • NAATs are superior other available diagnostic tests in “overall sensitivity, specificity, and ease of specimen transport;”
    • The use of “NAAT to detect chlamydia and gonorrhea except in cases of child sexual assault involving boys and rectal and oropharyngeal infections in prepubescent girls” is supported by evidence; and
    • Only NAATs that have been cleared by the FDA for detection of C. trachomatis and N. gonorrhoeae should be used “as screening or diagnostic tests because they have been evaluated in patients with and without symptoms”.
  • In 2009, the CDC published updated guidelines for the use of NAATs in the diagnosing Mycobacterium tuberculosis bacteria. The CDC recommended that “NAA testing be performed on at least one respiratory specimen from each patient with signs and symptoms of pulmonary TB for whom a diagnosis of TB is being considered but has not yet been established, and for whom the test result would alter case management or TB control activities.” Although it noted that “culture remains the gold standard for laboratory confirmation of TB and is required for isolating bacteria for drug-susceptibility testing and genotyping,” the guideline stated that “NAA testing should become standard practice for patients suspected to have TB, and all clinicians and public health TB programs should have access to NAA testing for TB to shorten the time needed to diagnose TB from one to two weeks to one to two days.”
  • For Bacterial Vaginosis: In 2021, the Centers for Disease Control and Prevention updated its guidelines on sexually transmitted infections. Regarding the diagnosis of bacterial vaginosis (BV), the guidelines stated:
    • “BV can be diagnosed by....clinical criteria (i.e., Amsel’s Diagnostic Criteria) or by determining the Nugent score from a vaginal Gram stain. Vaginal Gram stain, considered the reference standard laboratory method for diagnosing BV, is used to determine the relative concentration of lactobacilli …"
    • The guidelines state that multiplex PCR assays are available, but noted that traditional methods of BV diagnosis, including the Amsel criteria, Nugent score, and the Affirm VP III assay, remain useful for diagnosing symptomatic BV because of their lower cost and ability to provide a rapid diagnosis. The guidelines also stated that BV nucleic acid amplification tests should be used among symptomatic women only (e.g., women with vaginal discharge, odor, or itch) because their accuracy is not well defined for asymptomatic women.

Infectious Disease Society of America et al

Since 2008, the IDSA has partnered with various societies to publish nine recommendations regarding the use of NAATs to diagnose the viruses and infections discussed in this evidence review.

In 2018, the IDSA and the American Society for Microbiology published a guide on the diagnosis of infectious diseases. In this guideline, NAATs were recommended diagnostic procedures for Enterovirus, Hepatitis C, Hepatitis B, Cytomegalovirus, Herpes Simplex Virus, Human Herpesvirus 6, HIV, Influenza Virus, and Zika Virus. For bacterial vaginosis, NAATs were not recommended diagnostic procedures. In addition to providing guidance on diagnosing these diseases, the guidelines also provided recommendations on testing for other conditions by testing for common etiologic agents. The table below describes the condition for which the IDSA recommends NAATs for diagnosing etiologic agents.

Table. IDSA Recommended Conditions for Use of NAATs in Identifying Etiologic Agents of Other Conditions*

Etiologic Agents

Recommended Conditions for Use of NAATs in Diagnosis when Specific Etiologic Agents is Suspected

Bartonella spp

Bloodstream infections

Chlamydia pneumonia

Bronchiolitis, bronchitis, and pertussis; community- acquired pneumonia

Chlamydia trachomatis

Periocular structure infections/ conjunctivitis, orbital and periorbital cellulitis, and acrimal and eyelid infections; proctitis; epididymitis and orchitis; pathogens associated with cervicitis/ urethritis; pathogens associated with pelvic inflammatory disease and endometritis

Clostridioides (Clostridium) difficile

Gastroenteritis, infectious, and toxin- induced diarrhea

Cytomegalovirus

Pericarditis and myocarditisa; encephalitis; pneumonia in the immunocompromised host; esophagitis; gastroenteritis, infectious, and toxin- induced diarrhea; burn wound infectionsb

Enterovirus

Meningitis; encephalitis; brochiolitis, bronchitis, and pertussis; community- acquired pneumonia; gastroenteritis, infectious, and toxin- induced diarrhea

Herpes simplex virus

Meningitis; encephalitis; immunocompromised host; esophagitis; proctitis; pathogens associated with cervicitis/ urethritis; burn wound infectionb; periocular structure infections/conjunctivitis, orbital and periorbital cellulitis, and acrimal and eyelid infections; periocular structure infections/ keratitis; pharyngitis; genital lesions

HIV

Pericarditis and myocarditis; meningitisc; pharyngitisc

Human herpesvirus 6

Encephalitis

Influenza virus

Encephalitis; bronchiolitis, bronchitis, and pertussis; community- acquired pneumonia; hospital- acquired pneumonia and ventilator- associated pneumonia; pulmonary infections in cystic fibrosis

Legionella spp

community- acquired pneumonia; hospital- acquired pneumonia and ventilator-associated pneumonia; infections of the pleural space; surgical site infections

Mycobacteria species- both tuberculosis and NTM

Community- acquired pneumonia; infections of the pleural space; osteomyelitis

Neisseria gonorrhoeae

Pharyngitis; proctitis; native joint infection and bursitis; epididymitis and orchitis; pathogens associated with cervicitis/urethritis; pathogens associated with pelvic inflammatory disease and endometritis

Staphylococcus aureus

Burn wound infections for MRSA and S. aureus only ;trauma- associated cutaneous infections; surgical site infections

Streptococcus, group A

Pharyngitis

Trichomonas vaginalis

Pathogens associated with cervicitis/ urethritis; pathogens associated with pelvic inflammatory disease and endometritis

* The IDSA provided recommendations for many situations in which NAATs are recommended for diagnosing certain etiologic agents commonly seen, with the listed conditions noted under the Recommended Conditions for Use of NAATs in Diagnosis Column. HIV: human immunodeficiency virus; IDSA: Infectious Disease Society of America; MRSA: methicillin-resistant Staphylococcus aureus; NAAT: nucleic acid amplification test: NTM: nontuberculous mycobacteria.

a Recommended as first choice if available.

b Where applicable and laboratory-validated.

c The guidelines caution that NAAT is not 100% sensitive in individuals with established HIV infection due to viral suppression; therefore, if NAAT is used, subsequent serologic testing is recommended.

Use of NAATs for diagnosing Candida species, Gardnerella vaginalis, Streptococcus Group B, and Vancomycin-resistant enterococcus as etiologic agents was not recommended.

In 2017, the IDSA published clinical practice guidelines for the management of healthcare-associated ventriculitis and meningitis. When making diagnostic recommendations, the IDSA notes cultures as the standard of care in diagnosing healthcare-associated ventriculitis and meningitis, but that “nucleic acid amplification tests, such as PCR, on CSF may both increase the ability to identify a pathogen and decrease the time to making a specific diagnosis (weak, low).” (Strength of recommendation and quality of evidence established using the GRADE [Grading of Recommendations Assessment, Development and Evaluation] methodology.)

In 2008, the IDSA published clinical practice guidelines for the management of encephalitis. The following recommendations were made:

  • “Biopsy of specific tissues for culture, antigen detection, nucleic acid amplification tests (such as PCR), and histopathologic examination should be performed in an attempt to establish an etiologic diagnosis of encephalitis (A-III).” (Strength of recommendation level “A indicates good evidence to support recommendation for use.” Quality of evidence level III indicates “evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.”)
  • “Nucleic acid amplification tests (such as PCR) of body fluids outside of the CNS may be helpful in establishing the etiology in some patients with encephalitis (B-III).” (Strength of recommendation level B indicates “moderate evidence to support recommendation.” Quality of evidence level III indicates “evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.”)
  • “Nucleic acid amplification tests (such as PCR) should be performed on CSF specimens to identify certain etiologic agents in patients with encephalitis (A-III). Although a positive test result is helpful in diagnosing infection caused by a specific pathogen, a negative result cannot be used as definitive evidence against the diagnosis.”
  • The use of NAATs was recommended for diagnosing CMV, herpes simplex virus 1 and 2, Human herpesvirus 6, Bartonella henselae, Mycoplasma pneumoniae, and Mycobacterium tuberculosis.

In 2018, the IDSA and the Society for Healthcare Epidemiology of America (SHEA) published weak recommendations with low quality evidence for the use of NAATs to diagnose Clostridioides (Clostridium) difficile.

  • “The best-performing method (i.e., in use positive and negative predictive value) for detecting patients at increased risk for clinically significant C. difficile [CDI] infection” is use of a “stool toxin test as part of a multistep algorithm…rather than NAAT along for all specimens received in the clinical laboratory when there are no preagreed institutional criteria for patient stool submission.”
  • “The most sensitive method of diagnosis of CDI in stool specimens from patients likely to have CDI based on clinical symptoms” is use of “a NAAT alone or a multistep algorithm for testing…rather than a toxin test alone when there are preagreed institutional criteria for patient stool submission.”

In 2017, the IDSA published clinical practice guidelines for the diagnosis and management of infectious diarrhea. The following recommendations were made:

  • In situations where enteric fever or bacteremia is suspected, “culture-independent, including panel-based multiplex molecular diagnostics from stool and blood specimens, and when indicated, culture-dependent diagnostic testing should be performed” (GRADE: strong, moderate).
  • In testing for Clostridioides (Clostridium) difficile in patients >two years of age, “a single diarrheal stool specimen is recommended for detection of toxin or toxigenic C. difficile strain (e.g., nucleic acid amplification testing)” (GRADE: strong, low).
  • NAATs are not recommended for diagnosing CMV.
  • It was also noted that “clinical consideration should be included in the interpretation of results of multiple-pathogen nucleic acid amplification tests because these assays detect DNA and not necessarily viable organisms” (GRADE: strong, low).

In 2016, the IDSA published updated clinical practice guidelines for managing candidiasis. The guideline noted many limitations of PCR testing. No formal recommendation was made, but the guidelines did state that “the role of PCR in testing samples other than blood is not established.”

In 2020, the IDSA established a panel composed of eight members including frontline clinicians, infectious diseases specialists and clinical microbiologists who were members of the IDSA, American Society for Microbiology, Society for Healthcare Epidemiology of America (SHEA), and the Pediatric Infectious Diseases Society (PIDS). Panel members represented the disciplines of adult and pediatric infectious diseases, medical microbiology, as well as nephrology and gastroenterology. The panel created a coronavirus disease 2019 diagnosis guideline using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for evidence assessment; and, given the need for rapid response to an urgent public health crisis, the methodological approach was modified according to the GIN/McMaster checklist for development of rapid recommendations. The panel published recommendations for COVID-19 diagnosis in an online format, as when substantive new information becomes available the recommendations will require frequent updating. The current recommendations (December 23, 2020) support Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid testing for the following groups:

  • all symptomatic individuals suspected of having COVID-19;
  • asymptomatic individuals with known or suspected contact with a COVID-19 case;
  • asymptomatic individuals with no known contact with COVID-19 who are being hospitalized in areas with a high prevalence of COVID-19 in the community;
  • asymptomatic individuals who are immunocompromised and being admitted to the hospital, regardless of COVID-19 exposure;
  • asymptomatic individuals prior to hematopoietic stem cell transplant or solid organ transplantation, regardless of COVID-19 exposure;
  • asymptomatic individuals without known exposure to COVID-19 undergoing major time-sensitive surgeries;
  • asymptomatic individuals without a known exposure to COVID-19 who are undergoing a time-sensitive aerosol generating procedure (e.g., bronchoscopy) when personal protective equipment (PPE) is limited, and testing is available;
  • asymptomatic individuals without known exposure when the results will impact isolation/quarantine/personal protective equipment (PPE) usage decisions, dictate eligibility for surgery, or inform administration of immunosuppressive therapy.

The IDSA panel further recommends the following:

  • collecting nasopharyngeal swab, mid-turbinate swab, anterior nasal swab, saliva or a combined anterior nasal/oropharyngeal swab rather than oropharyngeal swabs alone for SARS-CoV-2 RNA testing in symptomatic individuals with upper respiratory tract infection or influenza like illness suspected of having COVID-19 (conditional recommendation, very low certainty of evidence).
  • nasal and mid-turbinate swab specimens may be collected for SARS-CoV-2 RNA testing by either patients or healthcare providers, in symptomatic individuals with upper respiratory tract infection or influenza like illness suspected of having COVID-19 (conditional recommendation, low certainty of evidence).
  • a strategy of initially obtaining an upper respiratory tract sample (e.g., nasopharyngeal swab) rather than a lower respiratory sample for SARS-CoV-2 RNA testing in hospitalized patients with suspected COVID-19 lower respiratory tract infection. If the initial upper respiratory sample result is negative, and the suspicion for disease remains high, the IDSA panel suggests collecting a lower respiratory tract sample (e.g., sputum, bronchoalveolar lavage fluid, tracheal aspirate) rather than collecting another upper respiratory sample (conditional recommendations, very low certainty of evidence)
  • performing a single viral RNA test and not repeating testing in symptomatic individuals with a low clinical suspicion of COVID-19 (conditional recommendation, low certainty of evidence).
  • repeating viral RNA testing when the initial test is negative (versus performing a single test) in symptomatic individuals with an intermediate or high clinical suspicion of COVID-19 (conditional recommendation, low certainty of evidence).
  • using either rapid RT-PCR or standard laboratory-based NAATs over rapid isothermal NAATs in symptomatic individuals suspected of having COVID-19 (conditional recommendation, low certainty of evidence).

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (NICE; 2008) updated its clinical guideline on antenatal care for uncomplicated pregnancies in 2019. Regarding the screening of asymptomatic bacterial vaginosis, the guidelines stated:

"Pregnant women should not be offered routine screening for bacterial vaginosis because the evidence suggests that the identification and treatment of asymptomatic bacterial vaginosis does not lower the risk of preterm birth and other adverse reproductive outcomes."

National Institute of Health et al

The National Institute of Health (NIH), CDC, and HIV Medicine Association of the Infectious Diseases Society of America (IDSA) published guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. The most recent update took place in 2022. In these guidelines, NAATs are discussed in the following situations:

  1. Bartonella species: For patients with suspected bacillary angiomatosis, serologic tests are the standard of care of diagnosing Bartonella infection. There are PCR “methods that have been developed for identification and speciation of Bartonella and are becoming increasingly available through private laboratories, as well as the CDC and may aid in diagnosis of Bartonella in freshly biopsied tissue samples or whole blood.
  2. Clostridioides (Clostridium) difficile: Detection of either the C. difficile toxin B gene, using NAAT, or the C. difficile toxin B protein, using an enzyme immunoassay, is required for diagnosis. PCR assays have high sensitivity and can detect asymptomatic carriers.
  3. Cytomegalovirus: For patients with suspected CMV disease, diagnosis is based on clinical symptoms and the presence of CMV in cerebral spinal fluid (CSF) or brain tissue, most often evaluated with PCR. “Viremia can be detected by PCR” however, "a negative serum or plasma PCR assay does not rule out CMV end-organ disease."
  4. Hepatitis B: The CDC, the United States Preventive Services Task Force, and the American Association for the Study of Liver Disease (AASLD) recommend that patients with HIV infection should be tested for hepatitis B; however, NAATs are not recommended for initial testing in patients with HIV.
  5. Hepatitis C: Patients with HIV are recommended to undergo routine hepatitis C screening, initially “performed using the most sensitive immunoassays licensed for detection of antibody to HCV in blood.” The use of NAATs are not mentioned for initial testing in patients with HIV.
  6. Herpes Simplex Virus: “HSV DNA PCR and viral culture are preferred methods for diagnosis of mucocutaneous lesions potentially caused by HSV.”
  7. Mycobacterium tuberculosis infection and disease:
  • “NAA tests provide rapid diagnosis of TB, and some assays also provide rapid detection of drug resistance.”
  • "NAA assays, if positive, are highly predictive of TB disease when performed on Acid-Fast Bacillus (AFB) smear-positive specimens. However, because nontuberculous mycobacterial infections (NTM)may occur in people with HIV with advanced immunodeficiency, negative NAA results in the setting of smear-positive specimens may indicate NTM infection and can be used to direct therapy and make decisions about the need for respiratory isolation."
  • "NAA tests are more sensitive than AFB smear, being positive in 50% to 80% of smear negative, culture-positive specimens and up to 90% when three NAA tests are performed. Therefore, it is recommended that for all patients with suspected pulmonary TB, a NAA test be performed on at least one specimen. NAA tests also can be used on extra pulmonary specimens with the caveat that the sensitivity is often lower than with sputum specimens."

U.S. Preventive Services Task Force Recommendations

See previous section for Hepatitis B USPSTF recommendations.

For Bacterial Vaginosis: The USPSTF (2020) recommendations on screening for BV in pregnancy have stated that:

“The USPSTF recommends against screening for bacterial vaginosis in pregnant persons who are not at increased risk for preterm delivery.” (Grade D recommendation)

“The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for bacterial vaginosis in pregnant persons who are at increased risk for preterm delivery.” (I statement)

KEY WORDS:

Bartonella henselae or quintana, Borrelia burgdorferi, Candida species, Chlamydia pneumonia or trachomatis, Clostridium difficile, Cytomegalovirus (CMV), Enterovirus, Vancomycin-resistant Enterococcus, Gardnerella vaginalis, Hepatitis B, Hepatitis C, Hepatitis G, Herpes simplex virus, Herpes virus-6, Human immunodeficiency virus 1 (HIV-1), Human immunodeficiency virus (HIV-2), Human papillomavirus (HPV), Influenza virus, Legionella pneumophila, Mycobacterium species, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycoplasma pneumonia, Neisseria gonorrhoeae, Respiratory Viral Panel, Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus, Streptococcus, Group A, Streptococcus, Group B, Trichomonas vaginalis, Human Herpes virus-6, MicroGenDX, MYCODART, BioFire, FilmArray GI Panel, FilmArray Respiratory Panel, GI panel, Respiratory Panel, ePlex, GIPP, BV, Bacterial Vaginosis, Aptima BV Assay, BD Max, Zika Virus, COVID-19, Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, Multitarget, Orthopoxvirus, Monkeypox, cowpox virus, vaccinia virus, Xpert® Xpress MVP, Xpert® CT/NG, Cepheid®, PreTect HPV-Proofer' 7, tick borne bacteria

APPROVED BY GOVERNING BODIES:

The U.S. Food and Drug Administration maintains a list of nucleic acid amplification tests (NAATs) that have been cleared by the Center for Devices and Radiological Health. These NAATs have been cleared for many of the microorganisms discussed in this review and may be reviewed on this site.

The table below summarizes the NAATs cleared for central nervous system panels when diagnosing meningitis and/or encephalitis, for panels when diagnosing gastroenteritis, and for respiratory panels.

Table. FDA Cleared Nucleic Acid Amplification Tests for Central Nervous System, Gastrointestinal, and Respiratory Panels

NAAT

Manufacturer

510(k) Number

Product Code

Meningitis/Encephalitis (CNS) Pathogen Panels

FilmArray Meningitis/Encephalitis Panel

BioFire Diagnostics, LLC (Salt Lake City, UT)

DEN150013, K160462

PLO

Gastroenteritis Pathogen Panels

xTAG Pathogen Panel (GPP)

Luminex Molecular Diagnostics, Inc. (Toronto, Ontario, CA)

DEN130003, K121454

PCH

Progastro SSCS Assay

Gen-Probe Prodesse, Inc.(Waukesha, WI)

K123274

PCH

Biocode Pathogen Panel

Applied Biocode (Santa Fe Springs, CA)

K190585

PCH

EntericBio Dx Assay

Serosep, Ltd (Annacotty, IE)

K182703

PCH

Filmarray Panel

BioFire Diagnostics, LLC (Salt Lake City, UT)

K140407, K160459

PCH

ProGastro SSCS

Hologic/Genprobe (Waukesha, WA)

K123274

PCH

BD MAX Enteric Bacterial Panel (EBP)

BD Diagnostics (Sparks, MD)

K170308

PCH

Verigene Enteric Pathogen Panel (EP)

Nanosphere, Inc. (Northbrook, IL)

K142033, K140083

PCH

xTAG Gastroenterology Pathogen Panel(GPP) Multiplex Nucleic Acid-Based Assay System

Luminex Molecular Diagnostics, Inc. (Toronto, Ontario, CA)

K121894

PCH

FilmArray GI Panel

BioFire Diagnostics, Inc. (Salt Lake City, UT)

K140407

PCH

Respiratory Viral Panels

ID-TAG Respiratory Viral Panel Nucleic Assay System

Luminex Molecular Diagnostics, Inc. (Toronto, Ontario, CA)

DEN070013, K063765

PCH

Biocode Respiratory Pathogen Panel

Applied BioCode, Inc. (Santa Fe Springs, CA)

K192485

PCH

Nxtag Respiratory Pathogen Panel

Luminex Molecular Diagnostics, Inc. (Toronto, Ontario, CA)

K193167

PCH

xTAG Respiratory Virus Panel (RVP)

Luminex Molecular Diagnostics, Inc. (Toronto, Ontario, CA)

K081483

PCH

Qiastat-Dx Respiratory Panel

QIAGEN GmbH (Germantown, MD)

K183597

PCH

xTAG Respiratory Virus Panel FAST

Luminex Molecular Diagnostics, Inc. (Toronto, Ontario, CA)

K103776

PCH

eSensor® Respiratory Virus Panel (RVP)

Clinical Micro Sensors, Inc.(Carlsbad, CA)

K113731

PCH

Verigene Respiratory Pathogens Plus Nucleic Acid Test

Nanosphere, Inc. (Northbrook, IL)

K103209

PCH

BioFire FilmArray Respiratory Panel (RP)

BioFire Diagnostics, Inc. (Salt Lake City, UT)

K123620

PCH

CNS: central nervous system; DEN: de novo; FDA: Food and Drug Administration. NAAT: nucleic acid amplification tests.

In October 2016, the Food and Drug Administration completed a review of a de novo request for classification of the BD Max™ Vaginal Panel (Becton, Dickinson). The test was granted class II designation, marketing authorization, and is indicated for the direct detection of DNA targets from bacteria associated with bacterial vaginosis (DEN160001). In 2019, the Aptima BV Assay (Hologic, Inc.) received 510(k) clearance (K190452) with the BD Max as the predicate device. Product code: PQA, NSU, PMN.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Act for high-complexity testing.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will review for medical necessity.

CURRENT CODING:

*See Policy Section

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  52. Nugent RP, Krohn MA, Hillier SL. Reliability of diagnosing bacterial vaginosis is improved by a standardized method of gram stain interpretation. J Clin Microbiol. Feb 1991; 29(2): 297-301.
  53. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis., 2015 Dec 19; 62(4).
  54. Pierce VM, Hodinka RL. Comparison of the GenMark Diagnostics eSensor respiratory viral panel to real-time PCR for detection of respiratory viruses in children. J Clin Microbiol 2012; 50(11):3458-65.
  55. Puopolo KM, Lynfield R, Cummings JJ et al. Management of Infants at Risk for Group B Streptococcal Disease. Pediatrics, 2019 Jul 10; 144(2).
  56. Recommendations for the Laboratory-Based Detection of Chlamydia trachomatis and Neisseria gonorrhoeae 2014. CDC MMWR. Published 3/14/14. https://www.cdc.gov/std/laboratory/2014labrec/2014-lab-rec.pdf. Accessed May 10, 2022.
  57. Richter SS, Otiso J, Goje OJ, et al. Prospective Evaluation of Molecular Assays for Diagnosis of Vaginitis. J Clin Microbiol. Dec 23 2019; 58(1).
  58. Riddle MS, DuPont HL, Connor BA. ACG Clinical Guideline: Diagnosis, Treatment, and Prevention of Acute Diarrheal Infections in Adults. Am J Gastroenterol. May 2016; 111(5): 602-22.
  59. Rumyantseva T, Shipitsyna E, Guschin A, et al. Evaluation and subsequent optimizations of the quantitative AmpliSens Florocenosis/Bacterial vaginosis-FRT multiplex real-time PCR assay for diagnosis of bacterial vaginosis. Apmis. Dec 2016; 124(12):1099-1108.
  60. Rumyantseva TA, Bellen G, Romanuk TN, et al. Utility of microscopic techniques and quantitative real-time polymerase chain reaction for the diagnosis of vaginal microflora alterations. J Low Genit Tract Dis. Jul 11 2014.
  61. Sattar SBA, Singh S. Bacterial Gastroenteritis. [Updated 2020 Aug 11]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK513295/. Accessed May 5, 2021.
  62. Schwebke JR, Gaydos CA, Nyirjesy P, et al. Diagnostic Performance of a Molecular Test versus Clinician Assessment of Vaginitis. J. Clin. Microbiol., 2018 Apr13; 56(6).
  63. Schwebke JR, Hobbs MM, Taylor SN et al. Molecular testing for Trichomonas vaginalis in women: results from a prospective U.S. clinical trial. J Clin Microbiol 2011; 49(12):4106-11.
  64. Schwebke JR, Taylor SN, Ackerman R, et al. Clinical Validation of the Aptima Bacterial Vaginosis and Aptima Candida/Trichomonas Vaginitis Assays: Results from a Prospective Multicenter Clinical Study. J Clin Microbiol. Jan 28 2020; 58(2).
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POLICY HISTORY:

Medical Policy Panel, September 2013

Medical Policy Group, November 2013 (2): New Policy

Medical Policy Administration Committee, November 2013

Available for comment November 20, 2013 through January 4, 2014

Medical Policy Panel, September 2014

Medical Policy Group, September 2014 (1): Updated Description, Policy statement, Key Points, Coding and References related to adding gastrointestinal pathogen panel (new CPT codes 87505-87507) as investigational, and adding new HPV probe CPT codes 87623-87625, which are considered medically necessary, all new codes effective 1/1/15. For annual coding, placed deleted codes under previous coding section.

Medical Policy Administration Committee, October 2014

Medical Policy Panel, February 2016

Medical Policy Group, May 2017 (3): Updates to Description, Key Points, Key Words, Approved Governing Bodies, & References; multiple coverage changes added to Policy statements

Medical Policy Administration Committee, June 2017

Available for comment May 23 through July 6, 2017

Medical Policy Group, July 2017 (3): Updated CPT code 87476 as medically necessary on coverage table under Policy Section

Medical Policy Panel, December 2017

Medical Policy Group, January 2018 (3): Updates to Description, Key Points & References; removed Previous Coding section for codes deleted 12/31/14; added central nervous system pathogen panel, ENT/pulmonary panel & nail panel to list of tests considered investigational; no change in intent of policy statements.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2019 Updates to Description, Key Points & References. Added previous coding section for codes: 87470, 87477, 87515-deleted 1/1/18 and removed them from Table 1, added PLA code 0068u-new code effective 10/1/18. Added key word: MYCODART. Removed the following from investigational policy statement: Central nervous system pathogen panel, ENT/pulmonary panel, Nail panel. Added to Table 2 (CPT Codes for Nucleic Acid Probes): Central nervous system pathogen panel, CPT code 87483 to amplified probe column.

Medical Policy Group, June 2019: July 2019 quarterly coding update. Added new CPT codes 0097U and 0098U – 0100U to Table 1 under Policy section. Added Key Words BioFire, FilmArray GI Panel, FilmArray Respiratory Panel, GI panel, Respiratory Panel.

Medical Policy Group, July 2019 (9): Added CPT code 87634 to Table 1 under Policy section for Respiratory Virus Panel.

Medical Policy Group, September 2019: October 2019 quarterly coding update.  Added new CPT codes 0112U and 0115U to the Policy section. Added Key Word ePlex.

Medical Policy Group, November 2019: 2020 Annual Coding Update. Added new CPT code 0151U code to the Policy section.

Medical Policy Group, December 2019 (9): Updated policy section dated January 15, 2020 and after to include criteria for gastrointestinal pathogen panels. Removed policy section dated January 1, 2014 through November 30, 2016. Removed 2015 coding information statement from policy section. Added key word: GIPP

Medical Policy Administration Committee, January 2020

Available for comment: December 13, 2019 through January 26, 2020.

Medical Policy Panel, December 2019

Medical Policy Group, January 2020 (9): 2019 Updates to information contained within policy regarding BV. Description, Key Points, Regulatory Status updated with BV information. Key words added: BV, Bacterial Vaginosis, Aptima BV Assay, BD Max. No change to policy statement.

Medical Policy Panel, February 2020

Medical Policy Group, March 2020 (9): 2020 Updates to Description, Key Point, References. Key Words added: Zika Virus. Policy statement updated: Zika virus direct or amplified probe without quantification medically necessary indication added to table 1 (this is not a change in stance); Chlamydia pneumoniae direct or amplified probe without quantification medically necessary (this is a change in stance from previous investigational stance) added to table 1; Infectious agent detection and identification AND infectious disease probe investigational statement added to table 1. Added CPT codes 0112U, 0140U, 0141U, 0142U, 87662

Medical Administration Policy Committee, April 2020.

Available for comment, March 24, 2020 through May 8, 2020.

Medical Policy Group, May 2020 (9): Added CPT code 0202U due to Ad Hoc Coding Update related to COVID.

Medical Policy Group, June 2020 (9): For clarification, added the following bullet point to policy statement: individuals with chronic diarrhea do not meet medical necessity for GIPP testing. For clarification, added definition of acute, persistent, and chronic diarrhea. No change to intent of policy statement.

Medical Policy Panel, June 2020

Medical Policy Group, July 2020 (9): Updates to Key Points, References. Added CPT code 87635. Added key words: COVID-19, Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2. Policy statement updated to support diagnostic testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using NAAT.

Medical Policy Group, October 2020: 2021 Annual Coding Update. Added new CPT code 81513-81514 to the Policy section.

Medical Policy Panel, December 2020    

Medical Policy Group, February 2021: (9) 2021 Updates to Description, Key Points, Approved By Governing Bodies, References. Added Keyword: multitarget. Policy statement updated to add “Multitarget polymerase chain reaction testing for the diagnosis of bacterial vaginosis is considered investigational. (There is no single CPT Code for BV testing)”, for clarification, no change to policy intent.” Policy statement updated to remove “not medically necessary,” no change to policy intent.  Previous coding section (including codes 87470, 87477, 87515) removed.

Medical Policy Group, March 2021: Quarterly Coding Update.  Edited codes 0098U-0100U to state deleted date of 03/31/21.

Medical Policy Panel, June 2021

Medical Policy Group, June 2021 (9): 2021 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, August 2021 (9): Updated policy statement by removing investigational criteria from GIPP, effective August 17, 2021. Updated Key Points, References.

Available for comment August 17, 2021 through October 1, 2021.

Medical Policy Administration Committee August 2021.

Medical Policy Group, November 2021 (9): 2022 Annual Coding Update. Added new CPT codes 0301U, 0302U, 87154 to policy section.

Medical Policy Panel, December 2021

Medical Policy Group, December 2021 (9): 2021 Updates to BV Description, Key Points, References. No change to policy statement.

Medical Policy Group, March 2022 (9): Quarterly Coding Update.  Noted codes 0097U & 0151U deleted effective 4/1/22. Added code 0321U to current coding. Removed policy statement section dated “Effective for dates of service December 1, 2016 through January 14, 2020” & “Effective for dates of service on or after January 15, 2020 through March 31, 2020”. Edits for clarification made to policy statement section and CPT Codes for Nucleic Acid Probes table. No change to policy intent. Updated References.

Medical Policy Panel, June 2022

Medical Policy Group, June 2022 (9): Quarterly Coding Update. Added new CPT code 0323U, and vaginal panel 0330U to policy section. 2022 Updates to Key Points, Description, References. No change to policy statement.

Medical Policy Group, August 2022 (9): Added “effective for dates of service on or after July 26, 2022” section to policy statement to include medically necessary indication for CPT code 87593 (orthopoxvirus, amplified probe). Code is added per ad hoc coding update effective 7/26/22. Added key words: Orthopoxvirus, Monkeypox, cowpox virus, vaccinia virus. CPT code eff dates removed from table for clarity (no change to coverage intent).

Available for comment September 1, 2022 through October 16, 2022.

Medical Policy Administration Committee August 2022.

Medical Policy Group, September 2022 (9): Quartely Coding Update. Added new CPT codes 0352U, 0353U, 0354U to policy sections. Key words added: Xpert® Xpress MVP, Xpert® CT/NG, Cepheid®, PreTect HPV-Proofer' 7

Medical Policy Group, November 2022 (9): Added CPT codes 87468, 87469, 87478, 87484 to policy section. Added "tick-borne bacteria" to medically necessary statement in policy section. No change to intent to coverage intent. Key word added: tick borne bacteria


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

The technology must have final approval from the appropriate government regulatory bodies;

The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

The technology must improve the net health outcome;

The technology must be as beneficial as any established alternatives;

The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

In accordance with generally accepted standards of medical practice; and

Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

Not primarily for the convenience of the patient, physician or other health care provider; and

Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease